title: Biphasic responses in multi-site phosphorylation systems.
abstract: Multi-site phosphorylation systems are repeatedly encountered in cellular biology and multi-site modification is a basic building block of post-translational modification. In this paper, we demonstrate how distributive multi-site modification mechanisms by a single kinase/phosphatase pair can lead to biphasic/partial biphasic dose-response characteristics for the maximally phosphorylated substrate at steady state. We use simulations and analysis to uncover a hidden competing effect which is responsible for this and analyse how it may be accentuated. We build on this to analyse different variants of multi-site phosphorylation mechanisms showing that some mechanisms are intrinsically not capable of displaying this behaviour. This provides both a consolidated understanding of how and under what conditions biphasic responses are obtained in multi-site phosphorylation and a basis for discriminating between different mechanisms based on this. We also demonstrate how this behaviour may be combined with other behaviour such as threshold and bistable responses, demonstrating the capacity of multi-site phosphorylation systems to act as complex molecular signal processors.
authors.affiliation: Department of Chemical Engineering, Centre for Process Systems Engineering, Imperial College London, , South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Thapanar
authors.initials: T
authors.lastname: Suwanmajo
authors.forename: J
authors.initials: J
authors.lastname: Krishnan
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D008958:Models, Molecular; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism / Q000502:physiology*
chemical_list: D010770:Phosphotransferases; D010744:Phosphoric Monoester Hydrolases
keywords: enzyme sequestration; multi-site modification; non-monotonic response; shared enzyme; signal processing; substrate sequestration